The immune system in autism: What does microglia have to do with it?

Microglia
credit: Gerry Shaw, from Wikimedia Commons

While much of the research on postmortem autistic brains involves the principal information processing cell, the neuron, there are other cells in the brain that have a variety of functions. Astrocytes and microglia are two types of “glial” cells specific to the central nervous system. While astrocytes have multiple functions, such as contributing to the protective barrier between the blood and the brain, microglia appear to be the major immune cell of the brain. Microglia have enormous influence on brain development by regulating the number of neurons that are generated. In the mature brain, microglia mount the brain’s response to infection and also clear the brain of debris after damage, such as a stroke. An early finding studying the brains of people with autism was a marked increase in astrocyte and microglial activation in the brains of people with autism1. When that first paper was published in autism, it was assumed that this increase in microglial activity was due to a sustained inflammatory response.

Around the same time as that autism study was published, researchers around the world were starting to recognize a new function of microglia – to shape or “prune” brain cells2. Later, the crucial role of microglia in shaping cells, establishing connections and remodeling brain circuits was documented3. In other words, microglia are not just responding to injury but are active participants in the development of correct brain connections. They help to set up the circuits of the brain by strengthening appropriate cell-to-cell connections and by eliminating improper connections in the brain. Since a popular hypothesis is that autism involves either too many or too few connections in the brain, it is no surprise that the role of microglia in autism has been under new interpretation.

Using resources from Autism BrainNet, researchers at both UCLA4 and Johns Hopkins University5 examined how different types of genes are turned on or off. Both studies discovered that as the activity of genes associated with microglia went up, the activity of genes associated with neuronal function went down. Based on their data, they concluded that in autism, the function of microglia was to regulate the plasticity of brain cells associated with autism. The fact that microglia were turned on in autism may be the result of all the activities required to reshape, mold and reconnect cells that started in irregular patterns. Recently, an immune receptor called TREM2, which has been shown to be critical for cutting down the excess of neurons during early brain development, has been found to be reduced in the brains of people with autism6. So, microglia and their activities to ensure that the brain is connected properly may be a critical piece in our understanding of the causes of autism.

Donna Werling, an investigator at the University of California at San Francisco (UCSF), has examined how gender may influence the activation of microglia. She and her colleagues have discovered that some genes associated with microglial activation are increased in males, and others are increased in females7. This is in contrast to autism genes, which are equally expressed in males and females with autism spectrum disorder (ASD). Some of these microglial genes may be turned on as the result of constantly reshaping and maintaining the autism brain. They may also be activated due to the presence of psychiatric comorbidities or the constant stress of having a neurodevelopmental disorder. However, it seems they are not turned on because of a focal injury or toxicological process. Microglial activation represents the constant rewiring, reshaping, modeling, and restructuring of brain cells that are functioning differently in people with ASD7. Dr. Werling’s research shows that the different responses of microglia in male and female brains may contribute to our understanding of why more males are diagnosed compared to females.

Studies like those described above are only possible by studying the brains of people with autism. Thanks to all of you who have signed up for the Autism BrainNet newsletter to learn more about why this program is so important.

References:

1. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of neurology. 2005;57(1):67-81.
2. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314-1318.
3. Neale BM, Kou Y, Liu L, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485(7397):242-245.
4. Voineagu I, Wang X, Johnston P, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380-384.
5. Gupta S, Ellis SE, Ashar FN, et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nature communications. 2014;5:5748.
6. Filipello F, Morini R, Corradini I, et al. The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity. Immunity. 2018;48(5):979-991 e978.
7. Werling DM, Parikshak NN, Geschwind DH. Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat Commun. 2016;7:10717.